Lynch syndrome

Background

• Also known as hereditary nonpolyposis colorectal carcinoma (HNPCC)

• Lynch syndrome preferred term since most patients will develop one or several adenomatous polyps

Pathogenesis

• Caused by inactivation of DNA genes responsible for mismatch repair (MMR)
  • MMR genes (4):
    • MLH1
    • MSH2
    • MSH6
    • PMS2
      • Mutations in MLH1 and MSH2 account for up to 90% of LS cases
        • Alterations affecting the normal function of these genes results in an accumulation of DNA errors and increases the potential for cancer development
• Autosomal dominant
  • NCI definition: autosomal dominant inheritance is a way a genetic trait or condition can be passed down from parent to child. One copy of a mutated (changed) gene from one parent can cause the genetic condition. A child who has a parent with the mutated gene has a 50% chance of inheriting that mutated gene.[1]

Phenotype

• Increased risk of cancer
  • LS cancers form only after a second hit (by one of several genetic damage mechanisms) occurs within somatic tissue, which causes loss of function to the normal (wild-type) allele inherited from the unaffected parent
    • This results in total loss of DNA MMR activity in that cell and subsequent microsatellite instability.
  • Associated malignancies (11):
    1. Colorectal (20-80%) (most common)
    2. Gynecologic
       1. Endometrial (15-60%) in females (second most common)
       2. Ovarian cancer (1-38%) in females
    3. Urologic
       1. Urothelial (1-18%), includes upper urinary tract and bladder
       2. Prostate
       3. Adrenal§
    4. Other gastrointestinal
       1. Gastric cancers (1-13%)
       2. Hepatobiliary
       3. Small bowel
    5. Skin
       • Sebaceous adenoma, sebaceous epithelioma, sebaceous adenocarcinoma, keratoacanthoma, and squamous cell carcinoma[2]
    6. Brain
    7. Inconsistent: Pancreas, breast, (prostate)

Diagnosis and Evaluation

• Clinical criteria: Amsterdam II criteria, Revised Bethesda Guidelines
• Models
• Tumour testing: microsatellite instability, immunohistochemistry

Screening

• Recommended screening[3]
  • Colonoscopy
  • Pelvic exam with endometrial sampling
  • Transvaginal ultrasound (ovarian)
  • Esophagogastroduodenoscopy with biopsy of the gastric antrum
  • Urinalysis
    • Limited data to support urinary screening
  • Routine screening of the prostate and breast cancer is not recommended beyond what is advised for the general population

References

• Giardiello, Francis M., et al. "Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer." Gastroenterology 147.2 (2014): 502-526.
• Yurgelun, Matthew B., and Heather Hampel. "Recent advances in lynch syndrome: diagnosis, treatment, and cancer prevention." American Society of Clinical Oncology Educational Book 38 (2018): 101-109.